The proposed research is designed to determine the relationship between radiation-induced cutaneous toxicity and fatigue in African American versus Caucasian women with breast cancer. 2.5 million women have survived breast cancer and are currently living with cancer-affected life years. The NCI Cancer Related Fatigue committee states that fatigue is the most common and distressing symptom related to cancer and its treatment. Recent data suggest that radiation-induced fatigue may be related to bystander damage to normal cutaneous tissue. This radiation-induced cutaneous toxicity may in turn lead to an inflammatory response and the peripheral release of inflammatory cytokines, which have been shown to access the brain and lead to behavioral changes including fatigue. Differential sensitivity to the various steps from radiation to fatigue may lead to greater symptoms of fatigue in African American versus Caucasian women with breast cancer. Indeed, in separate studies, African American women have been found to experience greater cutaneous toxicity and greater malaise as a consequence of radiation treatment. The long-term objective of the proposed research is to reduce the consequences of cancer treatments by understanding the mechanisms involved and identifying patients at risk and pathways for treatment and prevention. In addition, we endeavor to understand these mechanisms and pathways as they relate to potential racial disparities. In the current study, we will determine the relationship between radiation-induced cutaneous toxicity and fatigue and explore the potential contribution of peripheral inflammatory responses to this relationship. The primary hypothesis of the proposed research is that radiation-induced cutaneous toxicity will be significantly correlated with radiation-induced fatigue over time and that African American women will exhibit increased radiation-induced fatigue as a consequence of increased cutaneous toxicity. In addition, we will explore the hypothesis that the relationship between radiation-induced cutaneous toxicity and fatigue is mediated by activation of peripheral inflammatory responses which may in turn contribute to racial disparities. One hundred women (50 African American and 50 Caucasian) will be studied before, during and after standardized external beam radiation therapy (50 Gy followed by a 10 Gy boost) for Stage 0-II breast cancer. At each study visit, fatigue will be measured using the Multidimensional Fatigue Inventory, and cutaneous toxicity will be assessed using innovative, ultrasound breast imaging technology. Inflammatory responses will be measured by plasma concentrations of inflammatory cytokines and their soluble receptors as well as the inflammatory signaling molecule, nuclear factor kappa B. The data gained will serve as a foundation for understanding the mechanisms of radiation- induced fatigue and the factors that may contribute to racial disparities. In addition, novel targets may be revealed for the development of new pharmacologic and/or behavioral strategies for the treatment and/or prevention of radiation-induced fatigue and its contribution to symptom burden in women with breast cancer. PUBLIC HEALTH RELEVANCE: Fatigue, skin thickening, fibrosis and edema are common acute and potentially long-term debilitating toxicities of breast cancer radiotherapy, which contribute to a symptom burden that can persist into survivorship and impair quality of life. Differential sensitivity to the various steps linking radiation-induced skin toxicity to fatigue including an increased sensitivity to radiation-induced inflammatory responses may explain greater morbidity in African American versus Caucasian women as a result of breast cancer radiotherapy. The overall objective of the proposed research is to reduce the consequences of radiation treatment as well as racial disparities by understanding the mechanisms involved and identifying potential pathways for prevention and treatment intervention.